Project Details
Projekt
Ferroptosis induction as a novel treatment concept for relapsed childhood cancers
Applicant
Privatdozent Dr. Frank Westermann
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461704818
Treatment of relapsed childhood cancer is still a major challenge for pediatric oncologist, because current treatment concepts largely fail due to multi-drug resistance of cancer cells. More recently, large cancer genome sequencing studies have identified driver mutations involved in cancer initiation and progression and molecularly targeted treatment concepts addressing these cancer-specific mutations have been developed. However, treatment response and prolonged overall survival following these molecularly targeted treatments are rare. Therefore, novel treatment concepts are urgently needed that specifically target vulnerabilities that are mechanistically linked to oncogenic alterations. Here, we propose the development of treatment concepts using induction of ferroptosis, a novel type of regulated cell death (RCD), for relapsed childhood cancer. We will initially focus on childhood neuroblastoma, an embryonal tumor arising in progenitor cells of the peripheral sympathetic system, as a prototypic model system for MYCN/MYC-driven cancer types. We have shown in a previous study that MYCN mediates addiction to the amino acid cysteine and sensitizes to ferroptosis in this cancer type. The high cysteine demand of MYCN-amplified neuroblastoma is met by uptake and MYCN-induced transsulfuration of methionine to cysteine. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of glutathione, thus creating an Achilles’ heel in these highly malignant cancer cells. We will systematically explore molecular mechanisms of this novel metabolic cancer vulnerability. We will address the following specific aims (1) rationalize the impact of cyst(e)ine uptake, cysteine synthesis via transsulfuration (methionine-to-cysteine conversion) and cysteine catabolism on the activity of the glutathione-GPX4 system controlling ferroptosis in ferroptosis-sensitive vs. -resistant cancer cells, (2) we will explore treatment concepts targeting vulnerabilities inducing ferroptosis in various preclinical in vitro and in vivo tumor models, (3) we will define biomarkers for ferroptosis-sensitive and -resistant neuroblastoma subtypes, which will be further tested in large data sets of relapse childhood cancers (>1200 cases, INFORM) to test our concepts on other childhood cancer entities, (4) we will develop in vivo ferroptosis response biomarkers applicable in clinical trial settings. In summary, our proposal will address the potential of targeted ferroptosis induction in childhood cancers and define a roadmap for the application of this treatment concept in clinical trials.
DFG Programme
Priority Programmes
